Sevoflurane, whose chemical name is fluoromethyl 2,2,2-(trifluoro-1-trifluoromethyl)ethyl ether, was developed for use as an inhalation anesthetic.
The first reference, which describes the preparation of sevoflurane, is British patent GB 1,250,928, which describes the synthesis of 1,3-polyhalo-2-propyl ethers and the use of the same as anesthetics. The process employed consists of preparing the intermediate Sevochlorane, by free radical chlorination of 1,1,1,3,3,3-hexafluoro-2-propyl methyl ether with gaseous chlorine and luminous irradiation. This free radical chlorination results in a very low yield, being the practical yield in obtaining sevoflurane at the end of the process approximately 30% of the theoretical value. Sevoflurane is obtained by the reaction of sevochlorane with potassium fluoride in tetrahydrothiophene dioxide, commercially known as sulfolane, employing heating.
The vast majority of the commercial processes preferred for the preparation of sevoflurane rely on the use of hexafluoroisopropanol (HFIP) as starting material.
There are processes described in the literature in which sevoflurane is obtained directly from hexafluoroisopropanol without involving intermediates. This is the case, for example, of the processes for the synthesis of sevoflurane described in U.S. Pat. Nos. 4,250,334 and 4,469,898.
U.S. Pat. No. 4,250,334 describes a method for the synthesis of sevoflurane, consisting of the reaction of hexafluoroisopropanol with a mixture of hydrofluoric acid, paraformaldehyde and a dehydrating agent. Although it is a “one pot” method, during the production of sevoflurane and its subsequent distillation, a large quantity of hexafluoroisopropanol is co-distilled with the product, which results in large losses of this reagent, which is also an impurity, whose removal in posterior purification steps is critical, and difficult to accomplish. In addition to this inconvenience, the formation of side products is elevated, being that the final product is obtained, in an appropriate degree of purity, only after various purifications steps by fractional distillation.
U.S. Pat. No. 4,469,898 describes the synthesis of sevoflurane from hexafluoroisopropanol, hydrofluoric acid and a desiccating agent, in special equipment where unconsumed hexafluoroisopropanol is recycled. Various desiccating agents are employed such as sulfuric, phosphoric, trifluoromethanesulfonic acids, etc. The reported yields for this process are low and the isolated product presents low purity.
Particularly useful for the preparation of sevoflurane are those processes, which first prepare the intermediate sevochlorane, followed by fluorination through a halogen exchange reaction.
U.S. Pat. No. 6,100,434 describes the synthesis of sevoflurane through the preparation of sevochlorane and subsequent fluorination of this intermediate with potassium fluoride in a high molecular weight solvent. Sevochlorane is prepared from hexafluoroisopropanol, aluminum trichloride and 1,3,5-trioxane. An excess of aluminum trichloride in the reaction medium results predominantly in the formation of 2,2′-[methylenebis(oxy)]bis-(1,1,1,3,3,3-hexafluoropropane)—hereinafter denominated P1. The reaction is interrupted by addition of a 6N HCl solution to decompose the gel of hydroxydichloroaluminate. The authors relate that the isolated product contained 95% sevochlorane, <5% of P1 and <1% of polyacetals of higher molecular weight. The crude yield described was 87%. Among the disadvantages of this process is the fact that large quantities of aluminum trichloride must be handled, which is a highly hygroscopic solid and whose reaction with atmospheric humidity or with residual water present tends to be violent. The fact that this reagent easily reacts with water, resulting in the formation of acidic gasses, causes a reduction in its content, compromising considerably the yield of the reaction and the purity of the isolated product. The addition of a 6N hydrochloric acid solution to interrupt the reaction is an additional disadvantage of the process, violently elevating the reaction temperature, resulting in partial product loss by decomposition, volatilization and polymerization. Finally, this reaction generates as a residue, an aqueous phase containing hydroxyaluminates that require incineration for disposal, incurring additional costs.
U.S. Pat. No. 6,245,949 describes the synthesis of sevoflurane by the reaction of hexafluoroisopropanol with dimethoxymethane and the resulting product is submitted to reaction with aluminum trichloride and potassium fluoride. Once again there is the disadvantage of working with aluminum trichloride, which is hygroscopic and easily inactivated in the presence of humidity. The yield of the process is quite low, being declared by the author as 50%.
U.S. Pat. No. 6,271,422 describes the synthesis of sevoflurane by fluoromethylation of alcohols via decarboxylative halogenation. In this way, hexafluoroisopropanol is submitted to reaction with ethyl alpha-bromoacetate providing alpha-(hexafluoroisopropoxy) acetic acid in a yield of 66%. This intermediate is subjected to reaction with the highly toxic lead tetra-acetate, using the carcinogenic benzene as the solvent. In the reaction sequence, the homogeneous benzene/sevochlorane solution, which is inseparable by distillation, is reacted with potassium fluoride providing at the end of the process sevoflurane with a low yield of 28%.
U.S. Pat. No. 5,886,239 describes the synthesis of sevoflurane by reacting sevochlorane with the salt obtained from the reaction between sterically hindered tertiary amines, such as di-isopropylethylamine, and hydrofluoric acid. The process described is incomplete and results in low purity sevoflurane, which requires various purifications steps by fractional distillation to obtain a level of purity necessary for clinical use, which reduces considerably the yield declared by the inventors.
Various other references exist which describe the synthesis of sevoflurane employing uncommon reagents, or by way of processes, which are not industrially applicable due to their complexity or low yields.
The processes, which involve the reaction of hexafluoroisopropanol with the formation of the intermediate sevochlorane, are of particular interest. However, up to the present moment, there is no description of an efficient process for both steps, which can be easily adapted to commercial production of sevoflurane of high purity and yield.
Employing the processes described up to the present moment, the production of sevochlorane is problematic due to incomplete reactions with very low yields, or it requires difficult to handle or highly toxic reagents, or results in a product containing impurities difficult to separate.
For the conversion of sevochlorane to sevoflurane, in general, potassium fluoride (KF) is employed in a halogen exchange reaction. This reaction may result in low yields of sevoflurane due to parallel reactions, which result in elimination, hydrolysis and polymerization by-products.
Many of the processes which involve the synthesis of sevoflurane by reaction of sevochlorane with potassium fluoride (KF) employ between 2.5 and 7.0 equivalents of potassium fluoride (KF) per equivalent of sevochlorane and heating of the reaction medium for more than three hours. This excess of potassium fluoride (KF) is responsible for the formation of fluoromethyl 2,2-difluoro-1-(trifluoromethyl) vinyl ether (compound A), which has been shown to be nephrotoxic in rats and whose presence should be controlled in the final product. Heating for prolonged times leads to decomposition of the sevochlorane present in the reaction medium generating HFIP and fluorinated acetals reducing the yield and difficulting the isolation of a product with above 99.97% purity.
The conversion of sevochlorane to sevoflurane may employ between 1 and 2 equivalents of KF per molar equivalent of sevochlorane when the reaction is conducted in the presence of water as solvent and a phase transfer catalyst as described in patent WO2006/055748, however, a larger concentration of KF is important to obtain a better yield and to minimize the formation of hydrolysis products of sevochlorane. The object of this patent application, is a process for the conversion of sevochlorane to sevoflurane in water, whereby less than 5% of the starting sevochlorane is hydrolyzed.
As such, there exists the necessity of a process for the preparation of sevoflurane from hexafluoroisopropanol with the formation of the intermediate sevochlorane with high purity and high yield, and efficient conversion of sevochlorane to sevoflurane by halogen exchange reaction in such a way that the resulting product is obtained in high yield and purity.